In an attempt to increase the in vivo effectiveness of macrophage activating factor (MAF) our laboratory has focused on the use of multilamellar liposomes as carrier vehicles for delivering MAF and other activating agents directly to the phagocytic cell. In order for liposomes to serve as vehicles for the delivery of compounds to monocytes and macrophages, they must bind to and become endocytosed by the cells. Phagocytosis of liposomes by human blood monocytes was influenced by the chemical composition and surface charge. Negatively charged vesicles consisting of phosphatidylcholine and phosphatidylserine admixed in a 7:3 mole ratio were rapidly and efficiently internalized. Incubation of human monocytes with these liposomes containing MAF, muramyl dipeptide (MDP) or MTP-PE (a lipophilic derivative of MDP) rendered them tumoricidal. However, these activated monocytes did not harm normal embryonic fibroblasts even under conditions of co-cultivation. Likewise, activated monocytes lysed HSV-2 infected but not uninfected fibroblasts. Any successful approach to the eradication of metastases not only must circumvent the biological heterogeneity and cellular resistance of neoplastic cells but it must also be able to selectively destroy tumor but not normal cells. We believe that tumoricidal macrophages fulfill all of these criteria and their activation in vivo may offer a novel approach in the treatment of metastatic tumors. The in situ activation of tumoricidal macrophages may thus provide an attractive approach for the treatment of disseminated cancer. The mechanism by which MAF activates monocytes is thought to involve a 2-step process. The first step is binding to surface receptors followed by internalization, and the second step is interaction with an intracellular site to bring about activation. Using rodent and human MAF, we have shown that species specific surface receptor binding can be bypassed using liposome-encapsulated MAF. Furthermore, it is our interpretation that MAF may have at least 2 separate "functional" parts of the molecule: one for cell surface binding and a second for initiating the activation process once internalized.